Features of selected syndromes

Question 1

Diagnostic features for NF1 (n=7)

Answer 1

• Six or more café au lait macules >5 mm in greatest diameter in prepubertal individuals and >15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas (Figure 2) of any type or one plexiform neurofibroma (Figure 3)
• Freckling in the axillary or inguinal regions
• Optic glioma
• Two or more Lisch nodules (iris hamartomas)
• A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis
• A first-degree relative (parent, sib, or offspring) with NF1 as defined by the above criteria

Question 2

Major diagnostic features for TSC (n=11)

Answer 2

• Angiofibromas (≥3) or fibrous cephalic plaque
• Cardiac rhabdomyoma
• Cortical dysplasias, including tubers and cerebral white matter migration lines
• Hypomelanotic macules (3 to >5 mm in diameter)
• *Lymphangioleiomyomatosis (LAM)
• Multiple retinal nodular hamartomas
• *Renal angiomyolipoma
• Shagreen patch
• Subependymal giant cell astrocytoma (SEGA)
• Subependymal nodules (SENs)
• Ungual fibromas (≥2)

Question 3

Minor diagnostic features for TSC (n=6)

Answer 3

• “Confetti” skin lesions (numerous 1- to 3-mm hypopigmented macules scattered over regions of the body such as the arms and legs)
• Dental enamel pits (>3)
• Intraoral fibromas (≥2)
• Multiple renal cysts
• Nonrenal hamartomas
• Retinal achromic patch

Question 4

Non-malignant extraintestinal manifestations of FAP (n=6)

Answer 4

• Osteomas
• Dental abnormalities
• Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
• Benign cutaneous lesions (include epidermoid cysts and fibromas)
• Desmoid tumors
• Adrenal masses

Question 5

Malignant extraintestinal manifestations of FAP (n=3)

Answer 5

• Hepatoblastoma
• Thyroid cancer
• Medulloblastoma

Question 6

Diagnostic criteria for Birt-Hogg-Dube syndrome

Answer 6

Major criteria

• Five or more fibrofolliculomas/trichodiscomas with at least one confirmed histologically
• Identification of a heterozygous pathogenic variant in FLCN

Minor criteria

• Multiple lung cysts. Bilateral basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax
• Early-onset renal cancer (age <50 years)
• Multifocal or bilateral renal cancer
• Renal cancer of mixed chromophobe and oncocytic histology
• First-degree relative with BHDS

Question 7

Cutaneous manifestations of Birt-Hogg-Dube syndrome

Answer 7

• fibrofolliculomas
• acrochordons
• angiofibromas
• oral papules
• cutaneous collagenomas
• epidermal cysts

Question 8

Diagnostic criteria for Gorlin syndrome

Answer 8

Major criteria

• Lamellar (sheet-like) calcification of the falx or clear evidence of calcification in an individual younger than age 20 years. Falx calcification is nearly always present and is visible on anteroposterior (AP) x-rays of the skull after age 20 years.
• Jaw keratocyst. Odontogenic keratocyst histologically; seen on orthopantogram as an area of translucency
• Palmar/plantar pits (≥2); particularly useful in diagnosis and more pronounced when the hands and feet are soaked in warm water for up to ten minutes. Pits may appear as white “punched-out” or pink “pin-prick” lesions.
• Multiple basal cell carcinomas (BCCs) (>5 in a lifetime) or a BCC before age 30 years. Provision needs to be made for decreased risk of BCC in individuals with dark skin and increased risk in those with light skin living in hot sunny climates, particularly those with type 1 Celtic skin and red hair, and of this group, particularly those with the common MC1R variant (rs1805007), which can modify age of onset for NBCCS [Yasar et al 2015].
• First-degree relative with NBCCS

Minor criteria

• Childhood medulloblastoma (also called primitive neuroectodermal tumor)
• Lympho-mesenteric or pleural cysts
• Macrocephaly (OFC >97th centile)
• Cleft lip/palate
• Vertebral/rib anomalies observed on chest x-ray and/or spinal x-ray: bifid/splayed/extra ribs; bifid vertebrae
• Preaxial or postaxial polydactyly
• Ovarian/cardiac fibromas
• Ocular anomalies (e.g., cataract, developmental defects, and pigmentary changes of the retinal epithelium)

Question 9

Diagnostic criteria for Cowden syndrome

Answer 9

Pathognomonic criteria

• Adult Lhermitte-Duclos disease
• Mucocutaneous lesions:
• –Trichilemmomas (facial)
• –Acral keratoses
• –Papillomatous lesions
• –Mucosal lesions

Major criteria

• Breast cancer
• Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer
• Macrocephaly
• Endometrial carcinoma

Minor criteria

• Other thyroid lesions (e.g., adenoma, multinodular goiter)
• Intellectual disability (IQ ≤75)
• Hamartomatous intestinal polyps
• Fibrocystic disease of the breast
• Lipomas
• Fibromas
• Genitourinary tumors (especially renal cell carcinoma)
• Genitourinary malformation
• Uterine fibroids